New uracil derivatives



t d S ws Pat n 3,137,690 NEW URACIL DERIVATIVES Rudolf Pfister, Basel,Switzeriand, assignor to Geigy Chemical Corporation, Ardsley, N.Y., acorporation of Delaware No Drawing. Filed June 22, 1962, Ser. No.204,610 Claims priority, application Switzerland June 23, 1961 6 Claims.(Cl. 260-260) The present invention concerns new uracil derivativeswhich have valuable pharmacological properties, as well as processes forthe production thereof and compositions containing these new uracilderivatives.

It has surprisingly been found that uracil derivatives of the formulawherein R represents hydrogen or lower alkyl,

R represents hydrogen or lower alkyl,

R represents alkyl or alkenyl having from at least 3 to at most 6 carbonatoms or phenyl, and

R represents hydrogen, halogen, hydroxyl or lower alkyl or lower alkoxy,

have valuable pharmacological properties, in particularanti-inflammatory, analgesic and antipyretic activity when administeredperorally or parenterally. Compounds of the Formula I in which R isisopropyl, also cause a great excretion of sodium and chlorine ionswithout increasing the normal excretion of potassium ions. In addition,compounds of the Formula I, particularly those having a hydrogen as Rare suitable as intermediate products for the production of otherpharmaceutical substances.

The term lower in relation with alkyl and alkoxy means radicals havingfrom 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, isopropyl, butyletc., methoxy, ethoxy etc.

In the compounds of the Formula I, R and R are, for example, hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, tert. butyl or isobutylradicals. R represents, e.g. n-propyl, isopropyl, n-butyl, isobutyl,sec. butyl, tert. butyl, n-amyl, isoamyl, tert. amyl, n-hexyl, allyl,methallyl, crotyl and phenyl.

Examples of substituents R are fluorine, chlorine or bromine, hydroxylor methyl, ethyl, n-propyl, isopropyl, tert. butyl, methoxy, ethoxy,n-propoxy, isopropoxy or nbutoxy in the orthometaor, preferably, in theparaposition.

More specifically, this invention concerns new uracil derivatives of thefollowing formula 0 N Br rQ R; N /=O wherein R is hydrogen, chlorine,bromine, hydroxy, methoxy or ethoxy, especially hydrogen or chlorine.

The pharmacological activity of compounds of this preferred class ofuracil derivatives according to the invention is merely illustrated bythe following data: 3- phenyl-S-isopropyl-6-methyl-uracil e.g. shows ina wellknown analgesic test [hotplate method, cf. Woolfe and McDonald, J.Pharm, Exper. Therap. 80, 300 (1940)], when administered orally in adosage of 200 mg./kg., a considerable prolongation of the reaction timeof about 97%, and when administered orally in a dosage of 400 mg./kg.,said prolongation is about 147%. The toxicity (DL of the same compoundis 4830 mg./kg. (mice p.o.).

Where in the following there is made reference to compounds of FormulaI, the preferred compound of the above defined Formula Ia are alwaysincluded.

To produce the new compounds of Formula I, a compound of the generalFormula II and/ or of an inert organic solvent, with a phenyl isocyanateof the formula (III) wherein R, has the meaning given above, andsubsequent ring closure of the so obtained reaction product of theformula by treating it with an alkaline condensing agent and, ifdesired, by treating a compound of the Formula I in which R, is hydrogenwith a reactive ester of a com pound of the formula wherein R representslower alkyl or lower alkenyl, the reaction being performed in thepresence of an acid binding agent, in order to introduce a radical Rwhich is different from hydrogen.

The reaction of compounds of the Formula II with those of the Formula HIis performed, for example, in the presence of pyridine or anothertertiary organic base such as triethylamine in an anhydrous inertorganic solvent such as, e.g. benzene, toluene, methylene chloride orchloroform, at room temperature or, if necessary, with heating. The ringis closed preferably without previous working up of the intermediateproduct of Formula IV. If the solvent used in the first step is stableto alkaline condensing agents, it can also be used as reaction medium inthe second step.

Ring closure is performed, e.g. by heating the intermediate product ofthe Formula IV with sodium hydride or with a sodium alcoholate inbenzene, toluene or xylene, by heating with an alkali alcoholate in alower alkanol or, finally, by heating with an aqueous/alcoholic alkalihydroxide solution. The compounds obtained as reac- Patented June 16,1964 tion products of the Formula I in which R; is hydrogen are solublein aqueous alkali hydroxide solution with formation of alkali metalsalts and they can be precipitated by acidification. They are furtherpurified by recrystallisation from suitable organic solvents.

The introduction of a lower alkyl radical R is performed in a simplemanner, e.g. by reacting a compound of the Formula I containing ahydrogen atom as R with a reactive ester of a lower alkanol or loweralkenol. This reaction is performed in aqueous alkali hydroxide solution or, in the presence of an acid binding agent such as, e.g.potassium carbonate, in a suitable organic solvent such as, eg acetoneor butanone, if necessary with heating. Suitable reactive esters oflower alkanols or lower alkenols are, e.g. methyl bromide, methyliodide, ethyl bromide, n-propyl bromide, crotyl bromide, dimethylsulphate, diethyl sulphate or p-toluene sulphonic acid methyl ester.

Starting materials of the Formula II such as e.g. B- aminocrotonic acidethyl ester are known and others can be produced by methods known perse, e.g. by reaction of suitable a-substituted a-alkanoyl acetic acidlower alkyl esters with ammonia, lower alkylamines or loweralkenylamines. Numerous starting materials of the Formula III are alsoknown.

Compounds of the Formula I are obtained by a second process by reactinga compound of the formula wherein R R ,R and R have the meanings givenabove, with a carbonic acid derivative of the formula wherein Yrepresents chlorine, bromine or lower alkoxy and R has the meaning givenabove, treating the reaction product so obtained of the formula (VIII)with an alkaline condensing agent'to close the ring, and if desired,reacting the compound obtained of the Formula I wherein R is hydrogen,in the presence of an acid binding agent, with a reactive ester of acompound of the Formula V given above wherein R' has the meaning theregiven, in order to introduce a radical R diflFerent from hydrogen. v

The first step of the reaction is preferably performed in an inertorganic solvent such as, e.g. chloroforrm, benzene or toluene and, if Yis halogen, in the presence of an acid binding agent, e.g. a tertiaryorganic base such as pyridine or triethylamine, in the cold or, ifnecessary, with heating. The ring closure in the second step isperformed analogously to that described in the first process and, if"itis desired to introduce a lower alkyl radical R the procedure and thereaction components are the same as those given in the first process.

Starting materials of the Formula VI are obtained, e.g. by reactingacetoacetanilide and acetoacetanilides correspondingly substituted withregard to the meanings of R R and R1 with ammonia, lower alkylamines orlower alkenylamines. Examples of carbonic acid derivatives of theFormula VH' are carbonic acid ethyl ester chloride and methyl esterchloride (chloroformic acid methyl ester and ethyl ester) and alsodiethyl carbonate.

As ha'salready been mentioned above, compounds of the Formula I in whichR, is hydrogen, form salts most of which are water soluble, withinorganic bases, particularly alkali hydroxides, and also withpharmaceutically acceptable organic bases. Such compounds of the FormulaI can thus also be used in the form of aqueous solutions of their alkalimetal salts, e.g. for parenteral application.

Pharmaceutical compositions of the compounds of Formula I contain thesecompounds admixed with pharmaceutically acceptable organic and/orinorganic solid or liquid carriers suitable for enteral or parenteraladministration. They are used, for instance, in the form of tablets,drages, capsules or in liquid form as solutions, drops, suspensions oremulsions. Such compositions and preparations contain at least 0.5% ofthe active compounds of Formula I. Its percentage in these preparationsand compositions, of course, may be varied and may be between about 1%and about of the total weight of a dosage unit. Preferred compositionsand preparations are prepared in such a manner that a dosage unit formcontains between about 50 mg. and aboutSOO mg. of the compounds ofFormula I.

As excipients for solid compositions, substances which do not react withthe active compound can be employed such as, e.g. gelatine, sugar,dextrose, lactose, starches, stearic acid, magnesium or calciumstearate, methyl cellulose, talcum, cholesterol, Aerosil,polyvinylpyrrolidone or any other known carrier for the preparation ofsolid medicaments. As excipients for liquid preparations, polyvalentalcohols such as, e.g. glycerol, alkylene and polyalkylene glycols suchas, e.g. propylene glycol can be used. Water is especially used for thesoluble salts of the active compounds, for instance for the preparationof injectable solutions. Such injectable solutions may be sterilisedand/or contain auxiliary substances such as of the new compoundsaccording to the invention. Parts are given therein as parts by weightand their relationship to parts by volume is as that of grammes to cubiccentimetres. The temperatures are in degreescentigrade.

Example 1 (a) 55 .5 parts of or n butyl ,8 aminocrotonic acid ethylester are dissolved in 270 parts by volume of abs. benzene and 24.2.parts by volume of pyridine are added to the solution. 32.6 parts ofphenyl isocyanate are then added dropwise while stirring at 25. Thereaction mixture is then stirred for 30 minutes at the same temperatureand afterwards refluxed for 30 minutes.

([2) A solution of 6.9 parts of sodium in parts by volume of abs.ethanol is added at 25 to the solution obtained of the crude a-n-butyl-S-phenylureido-crotonic acid ethyl ester whereupon the main parts of thesolvent is distilled off. 270 parts by volume of abs. xylene are addedto the residue and the mixture is heated for 2 hours at 130. Aftercooling to room temperature, 100 parts of Water are added whereuponcrystals of B-phenyl-S-n-butyl- 6-methyl-uracil precipitate. Theprecipitation is com pleted by acidifying the aqueous solution. Afterrecrystal lisation from ethyl acetate, the new compound melts at Example2 A solution prepared according to Example 1(a) is first greatlyconcentrated and the residue together with 500 parts by volume ofethanol and 500 parts by volume of 2 N sodium hydroxide solution isheated for 30 minutes at 90 with vigorous stirring. After distillingoil? the ethanol,

the product isworked up with the addition of water as described inExample 1, whereupon the same compound as described in Example 1 isobtained.

Example 3 60.6 parts of u-isopropyl-B-aminocrotonic acid ethyl ester in300 parts by volume of benzene and 28.6 parts by volume of pyridine arereacted analogously to Example 1 with 38.7 parts by volume of phenylisocyanate. 17 parts of a suspension of sodium hydride in mineral oil1:1 is added at 25 while stirring to the solution obtained of the crudea-isopropyl- B-phenylureidocrotonic acid ethyl ester, whereupon thesolution is refluxed for 6 hours. The product is worked up analogouslyto example 1 beginning with the addition of water. The3-phenyl-5-isopropyl 6 methyl uracil obtained melts at 250 afterrecrystallisation from ethanol.

On reacting this compound with the calculated amount of sodium hydroxideor potassium hydroxide, e.g. in aqueous solution, the correspondingsodium or potassium salts is obtained after evaporation of the solvent.

On using 62.5 parts of p-acetoxy-phenylisocyanate, 3- (p-hydroxyphenyl)5 isopropyl 6 methyl-uracil is obtained; M.P. 320 (from glacial aceticacid). acetoxy group is hydrolysed during the working up under theconditions given.

Example 4 24.4 parts of 3 phenyl 5 isopropyl 6 methyluracil (see Example3) are dissolved, with heating, in 500 parts by volume of 2 N sodiumhydroxide solution. 9.5 parts by volume of dimethyl sulphate are addeddropwise at -5 and the mixture is stirred for 6 hours at The crystalswhich precipitate are filtered ofit' under suction, well washed andrecrystallised from 80% methanol. The 1,6-dimethyl 3 phenyl 5isopropyl-uracil obtained melts at 125.

Example 5 10 parts of 3 phenyl 5 isopropyl 6 methyl-uracil (see Example3) are dissolved in 400 parts by volume of Warm acetone. 100 parts ofanhydrous potassium carbonate and 3.9 parts by volume of ethyl bromideare then added at 25 whereupon the mixture is refluxed for :12 hours.After cooling, the salt mixture is 'filtered off, the filtrate isconcentrated and the residue is recrystallised from dilute ethanol. The1-ethyl-3-phenyl-5-isopropyl-6- methyl-uracil obtained melts at 138.

Example 6 19.9 parts of a-n-btuyl-fi-methylamino-crotonic acid ethylester are mixed with 100 parts by volume of benzene and 8.1 parts byvolume of pyridine. 10.9 parts by colume of phenyl isocyanate are addeddropwise to the mixture at room temperature whereupon the whole isrefluxed for 1 hour. A solution of 2.3 parts of sodium in 50 parts byvolume of abs. ethanol is then added at room temperature. The greaterpart of the solvent is then distillted off, 100 parts by volume ofxylene are added to the residue, and the reaction mixture is heated for3 hours at a bath temperature of 130140 while distilling ofl the ethanolliberated. 300 parts by volume of water are added to the cooled reactionmixture, the organic phase is dried, completely concentrated in vacuoand the residue recrystallised from methanol. The 1,6 dimethyl 3 phenyl5- n-butyl-uracil so obtained melts at 145.

Example 7 29.4 parts of a n butyl [3 amino crotonic acid anilide aredissolved in 200 parts by volume of chloroform and 20.2 parts by volumeof pyridine. 13.75 parts of chloroformic acid ethyl ester are addeddropwise at while stirring and the reaction mixture obtained is left tostand for 12 hours at 20. It is then washed with dilute hydrochloricacid and sodium carbonate solution and the chloroform solution whichremains is dried and evaporated. The syrupy residue is dissolved in 200parts The by volume of xylene and, in the presence of 3.12 parts ofsodium hydride, is refluxed for 4 hours. The reaction mixture is workedup, with the addition of water, as described in Example 1 whereupon thecompound described in that example is obtained.

The following compounds, for example, are obtained by the methodsdescribed in the above examples:

l-n-propyl 3 phenyl 5 isopropyl 6 methyl-uracil,

l-n-butyl 3 phenyl 5 isopropyl 6 methyl-uracil,

1,6 dimethyl 3 phenyl 5 isobutyl uracil, M.P. 183

1,6 dimethyl 3,5 diphenyl uracil, M.P. 122,

1,6 dimethyl 3 phenyl 5 sec.butyl uracil, M.P. 98.

The following compounds are also obtained analogously to Examples 1-3 or6-7:

Example 8 To produce 1000 tablets each containing 200 mg. of activesubstance of Formula I, the following are used:

G. Active substance of Formula I 200.0 Potato starch 55.0-125.0 Lactose55.0125.0 Aerosil, uncompressed 15.0-35.0

Polyvinylpyrrolidone 15 .0-3 0.0 Glycerine, Ph. Helv. V 5.0l5.0 Ethanol,q.s.

Potato starch 25.0-50L0 Talcum 25.0-50.0 Magnesium stearate 1.5-2.5

The total weight must be 500.0

To produce the powder mixture (A), first the uncompressed Aerosil ismixed with the dried potato starch. The active substance is then added,the whole is mixed and then sieved through a sieve (e.g. sieve V, Pharm.Helv. V). Finally the lactose is added and the powder mixture (A) issieved through a sieve. This powder mixture is then evenly moistenedwith the granulating solution (B) and the mass is granulated through asieve (e.g. sieve IV, Pharm. Helv. V). It is dried at about 30 for about16 hours. The dried granulate is again sieved through a sieve and thencarefully mixed with the substances given under (C). The mass soprepared is then compressed into tablets each weighing 500 mg. andcontaining 200 mg. of active substance.

In a specific example the following portions were used:

Ethanol, q.s.

Potato starch 35.0' Talcur'n 35.0 Magnesium stearate 1.5

500.0 Example 9 To produce-1000 tablets each containing 400 mg. ofactive substance of Formula I, the following are used:

G. Active susbtance of-Formulal. 400.0 Potato starch 56.0-120.0- Lactose56.0-1200 Aeros'il, uncompressed 24.0-56.0 Polyvinylpyrrolidone24.0-48.0 Glycerine 8.0-24.0- Ethanol, q.s.

Potato starch 40.0-80.0 Talcum 40.0-80.0 Aerosil, uncompressed 4.0-8.0Magnesium stearate 2.4-4.0

The total weight must be 800.0

The process for the'preparation is analogous to the process described inExample 8.

In a specific example the following portions were used:

To produce 1000 drages each containing 200 mg; of active substances ofFormula I the following are used:

G. Active substance 200.0 Potato starch; 7.5-18.0 Lactose 7.5-100Polyvinylpyrrolidone 8.4-14.0 Glycerine 2.8-8.4 Ethanol, q.s.

Potato starch 14.0-22.4 Talcum 14.0-22.4 Magnesium stear'ate 0.8-1.4

The total weight must' be 280.0

The components (A) are thoroughly mixed and sieved, then evenlymoistened with the granulating solution (B) andgranulated.Thisgranulateisdried, again sieved and then carefully mixed with thecompounds (C). From 8. this mixture the cores are compressed, each coreweighing- 280 mg. and containing-200 mg. of the active substance of theFormula I;

The drages are then finishedwith coating solution in the usual way. Inthis manner, drages having a total (i.e. core and coating) weight ofe.g. 385 mg. and containing 200 mg. of active substance of Formula I areobtained.

In a specific example the following portions were used:

G. l,6-dimethyl-3-phenyl-S-isopropyl-uracil 200.0 Potato starch 18.0Lactose 9.6

Polyvinylpyrrolidone 11.2 Glycerine 6.8 Ethanol, q.s.

Potato starch 16.5 Talcum M 16.5 Magnesium stearate 1.4

The cores prepared from these components are finished into drages with acoating solution from the following ingredients:

Lacca 3.00 Gum arabic 9.00 Dyestutf 0.03 Talcum 19.20 Aerosil 1.50 Sugar72.27

In Examples 8-10, the following compounds may be used alternatively:corn starch instead of potato starch, gelatine or sodiumcarboxyethylcellulose instead of polyvinylpyrrolidone, sorbitol 70%insteadof glycerine.

What is claimed is:

1. A member selected-from the group consistingof a compound of theformula N R. to N wherein R is a member selected from the groupconsisting of hydrogen and lower alkyl,

R is a member selected from the group consisting of hydrogen andmethyl,

R is a member selected from the group consisting of n-propyl, isopropyl,n-butyl, isobutyl, sec. butyl, amyl and phenyl, and

R is a member selected from the group consisting of hydrogen, methyl,methoxy, ethoxy, hydroxy, ch10- rine and bromine.

. 3-phenyl-5-isopropyl-6-methyl-uracil.

. 3-phenyl-5-isopropyl-1,6-dimethyl-uracil.

. 3-(p-chlorophenyl)-5-isopropyl-6rmethyl-uracil.

. 3-phenyl-5-n-butyl-6-methyl-uracil;

. 3-phenyl-5-isopropyl-l-n-propyl-6-methyl-uracil.

References Cited in the file of this patent FOREIGN PATENTS GreatBritain Oct. 19, 1955

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THEFORMULA